p16INK4A-dependent senescence in the bone marrow niche drives age-related metabolic changes of hematopoietic progenitors

Charlotte Hellmich, Edyta Wojtowicz, Jamie A. Moore, Jayna J. Mistry, Aisha Jibril, Benjamin B. Johnson, James G.W. Smith, Naiara Beraza, Kristian M. Bowles, Stuart A. Rushworth

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Abstract

Rapid and effective leukocyte response to infection is a fundamental function of the bone marrow (BM). However, with increasing age, this response becomes impaired, resulting in an increased burden of infectious diseases. Here, we investigate how aging changes the metabolism and function of hematopoietic progenitor cells (HPCs) and the impact of the BM niche on this phenotype. We found that, in response to lipopolysaccharide-induced stress, HPC mitochondrial function is impaired, and there is a failure to upregulate the TCA cycle in progenitor populations in aged animals compared with young animals. Furthermore, aged mesenchymal stromal cells (MSCs) of the BM niche, but not HPCs, exhibit a senescent phenotype, and selective depletion of senescent cells from the BM niche, as well as treatment with the senolytic drug ABT-263, improves mitochondrial function of HPCs when stressed with lipopolysaccharide. In summary, age-related HPC metabolic dysfunction occurs indirectly as a “bystander phenomenon” in the aging BM niche and can be restored by targeting senescent MSCs.

Original languageEnglish
Pages (from-to)256-268
Number of pages13
JournalBlood Advances
Volume7
Issue number2
DOIs
Publication statusPublished - 24 Jan 2023

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